HIV-1 vaccine efficacy trials and multiple animal studies, including those related to HIV-cure strategies, have shown that antibody interactions with cells - mediated by the antibody constant (Fc) region - can harness multiple aspects of the immune system to provide protection through mechanisms other than by neutralization. However, it is unknown whether candidate HIV-1 vaccine regimens that include induction of Fc-mediated antibody functions can be tested in the rhesus macaque (RM) nonhuman primate (NHP) in a way that can be translated to humans. In order to more effectively translate insights gained from RM studies to the clinic, there is a need to fully define the protective signatures of Fc-mediated antibody functions across rhesus macaques and humans. The work we propose will map antibody (Ab) and Fc-receptor (FcR) biology across humans and RMs with the goal of making observed protective responses in RMs more predictive of human responses, thus accelerating the most promising vaccine concepts to be advanced to the clinic with success. Our central hypothesis is that the RM model can be substantially improved for testing antibody-based interventions and vaccines through elucidation of key variables that impact species-specific Fc?R-dependent effector functions (i.e. antibody epitope specificity, immune complex formation, isotype/subclass, glycosylation, and FcR genotype/phenotype). To test this, we propose three synergistic, inter-related scientific Projects supported by three Cores to achieve the following Overall Aims: Overall AIM 1. Characterize effective anti-HIV-1 Fc-FcR biology across RM to humans. Overall AIM 2. Define HIV-1 virion and infected cell epitopes for antibody recognition. Overall AIM 3. Determine the Fv and Fc features of antibodies yielding maximal anti-HIV-1 activity.